A novel human tau knock-in mouse model reveals interaction of Abeta and human tau under progressing cerebral amyloidosis in 5xFAD mice

Abstract

Background Hyperphosphorylation and intraneuronal aggregation of the microtubule-associated protein tau is a major pathological hallmark of Alzheimer’s disease (AD) brain. Of special interest is the effect of cerebral amyloid beta deposition, the second main hallmark of AD, on human tau pathology. Therefore, studying the influence of cerebral amyloidosis on human tau in a novel human tau knock-in (htau-KI) mouse model could help to reveal new details on their interplay. Methods We studied the effects of a novel human htau-KI under fast-progressing amyloidosis in 5xFAD mice in terms of correlation of gene expression data with human brain regions, development of Alzheimer’s-like pathology, synaptic transmission, and behavior. Results The main findings are an interaction of human beta-amyloid and human tau in crossbred 5xFADxhtau-KI observed at transcriptional level and corroborated by electrophysiology and histopathology. The comparison of gene expression data of the 5xFADxhtau-KI mouse model to 5xFAD, control mice and to human AD patients revealed conspicuous changes in pathways related to mitochondria biology, extracellular matrix, and immune function. These changes were accompanied by plaque-associated MC1-positive pathological tau that required the htau-KI background. LTP deficits were noted in 5xFAD and htau-KI mice in contrast to signs of rescue in 5xFADxhtau-KI mice. Increased frequencies of miniature EPSCs and miniature IPSCs indicated an upregulated presynaptic function in 5xFADxhtau-KI. Conclusion In summary, the multiple interactions observed between knocked-in human tau and the 5xFAD-driven progressing amyloidosis have important implications for future model development in AD.

Updates on mouse models of Alzheimer’s disease

“…MAPT P290S KI developed murine tau aggregates. [ 102 – 104 ] MAPT KI x APP NLGF Faster spread of pathological tau (19 mo). Tau humanization did not affect A beta or neuroinflammation.…”

“…However, in the elevated plus maze tests, this mouse model spent less time in open arms than 5xFAD mice, indicating that human tau may partially rescue anxiety-like behaviors. Additionally, both MAPT KI mice with 5xFAD background and MAPT KI mice without 5xFAD background demonstrated better spatial learning abilities compared to 5xFAD mice in the Morris water maze, adding a layer of complexity to the effects of humanized tau on disease progression in 5xFAD background [ 104 ]. The MAPT KI mice with 5xFAD background also seemed to offset LTP impairments, with no statistically significant differences between these mice and wt controls [ 104 ].…”

“…Additionally, both MAPT KI mice with 5xFAD background and MAPT KI mice without 5xFAD background demonstrated better spatial learning abilities compared to 5xFAD mice in the Morris water maze, adding a layer of complexity to the effects of humanized tau on disease progression in 5xFAD background [ 104 ]. The MAPT KI mice with 5xFAD background also seemed to offset LTP impairments, with no statistically significant differences between these mice and wt controls [ 104 ]. Moreover, MAPT KI mice with 5xFAD background showed a negative correlation in AD gene expression when compared to 5xFAD and human co-expression network modules.…”

“…Moreover, MAPT KI mice with 5xFAD background showed a negative correlation in AD gene expression when compared to 5xFAD and human co-expression network modules. Gene set enrichment analysis (GSEA) revealed a significant enrichment in processes related to lysosomal function, oxidative phosphorylation, and phagocytosis in MAPT KI mice with 5xFAD background when compared to 5xFAD mice [ 104 ].…”

Rapidly reversible persistent long-term potentiation inhibition by patient-derived brain tau and amyloid ß proteins

“…Because pathological tau, mainly an intracellular protein, appears to spread readily intercellularly in the brain [15][16][17][18][19], studying the in vivo synaptotoxicity of tau in such extracts is considered to provide a potentially powerful means of elucidating disease pathophysiology, complementing other approaches (e.g. [20,21]).…”